title: Evaluation of brain anticholinergic activities of urinary spasmolytic drugs using a high-throughput radio receptor bioassay.
abstract: OBJECTIVE
  To compare the brain anticholinergic activities of five urinary spasmolytic drugs (USDs).
  
  
  METHODS
  In vitro study.
  
  
  METHODS
  Laboratory.
  
  
  METHODS
  None.
  
  
  METHODS
  A validated 96-well anticholinergic radio receptor bioassay using small incubation volumes (240 μL per well) was applied in the current study. The different USDs (tolterodine, oxybutynin, solifenacin, darifenacin, and 5-hydroxy-methyl-tolterodine (5-HMT; the active metabolite of fesoterodine) were dissolved in plasma in their respective therapeutic concentration ranges. The plasma samples were added directly to the wells of 96 filter plates, wherein the incubation, filtration, and counting of undisplaced radioactivity was performed. Standard curves with atropine were used as reference for estimations of anticholinergic activity (AA).
  
  
  RESULTS
  5-HMT and tolterodine displayed the highest AA of the tested USDs. In the middle of the therapeutic concentration range, the central anticholinergic potency of 5-HMT and tolterodine was more than 10 times as high as that of oxybutynin, solifenacin, and darifenacin. Darifenacin exhibited the lowest AA at therapeutic serum concentrations (< one-third the AA of oxybutynin and solifenacin).
  
  
  CONCLUSIONS
  Tolterodine and fesoterodine appear to have the highest pharmacodynamic potential to induce central anticholinergic side effects of the tested USDs. Darifenacin displayed the lowest AA, and combined with a low degree of brain distribution, it has probably the most favorable pharmacological profile of the USDs with respect to risk of cognitive impairment in older adults.
authors.affiliation: Department of Pharmaceutical Biosciences, School of Pharmacy, University of Oslo, Oslo, Norway.
authors.forename: Stine Mjåvatn
authors.initials: SM
authors.lastname: Jakobsen
authors.forename: Hege
authors.initials: H
authors.lastname: Kersten
authors.forename: Espen
authors.initials: E
authors.lastname: Molden
mesh_terms: D001559:Benzhydryl Compounds / Q000494:pharmacology; D001572:Benzofurans / Q000494:pharmacology; D001681:Biological Assay / Q000379:methods*; D001921:Brain / Q000187:drug effects*; D003072:Cognition Disorders / Q000139:chemically induced; D003408:Cresols / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008333:Mandelic Acids / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D010665:Phenylpropanolamine / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D011812:Quinuclidines / Q000494:pharmacology; D000069464:Solifenacin Succinate; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D000068737:Tolterodine Tartrate
chemical_list: D001559:Benzhydryl Compounds; D001572:Benzofurans; D003408:Cresols; D008333:Mandelic Acids; D018727:Muscarinic Antagonists; D011759:Pyrrolidines; D011812:Quinuclidines; D044005:Tetrahydroisoquinolines; D010665:Phenylpropanolamine; D000068737:Tolterodine Tartrate; C526675:fesoterodine; C101207:darifenacin; C005419:oxybutynin; D000069464:Solifenacin Succinate